CAREER: Determining and Tuning the Impact of Low-Level Metal-Based Nanoparticles on Actin Cytoskeleton in Normal and Cancer Cells
职业:确定和调整低水平金属基纳米颗粒对正常细胞和癌细胞肌动蛋白细胞骨架的影响
基本信息
- 批准号:2143972
- 负责人:
- 金额:$ 57.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:Standard Grant
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Nanomaterials may interact with human cells, due to the unintended release of nanomaterials into the environment (through air and water pollution), or intentionally in applications of nanomaterials for treating diseases such as cancer. Exposure of cells to nanomaterials can have dose-dependent beneficial or harmful effects. These effects are traditionally evaluated with biochemical assays such as cell viability and membrane integrity assays. However, these approaches neglect the impact of nanomaterials on the cell’s actin cytoskeleton, the “bone structure” of the cells. This CAREER project will generate new knowledge about how low-level metal-based nanoparticles impact the actin cytoskeleton in normal and cancer cells. The potential impact of this project will be in offering a sensitive and quantitative platform based on actin cytoskeleton of cells for nanomaterial safety assessment, thus enabling the establishment of regulatory and manufacturing frameworks for safe and sustainable nanomaterials. The project will also potentially lead to safe, effective, and versatile approaches for using nanomaterials to treat cancer metastasis (the cause of 90% of human cancer deaths). The research-integrated educational plan in this project places a strong emphasis on educating First-Generation College Students and Native American Students, two underrepresented groups in South Dakota currently exhibiting high dropout rates. Through well-planned summer research experiences, a total of 10 students from these two groups are expected to acquire valuable hands-on skills in the fields of chemistry, biology, materials science, and nanobiotechnology, as well as enhanced academic persistence in completing their STEM education. The PI will also conduct a workshop series entitled “SEE NANO” at Tribal Colleges and integrate visually appealing and scientifically interesting research results with Flipped Classroom Methodology to make STEM classrooms more enjoyable and engaging, thereby promoting active learning and retention in STEM fields.Most research on nanomaterial cytotoxicity relies on macroscopic biochemical assays, including cell viability and membrane integrity assays, without considering that nanoscale interactions with nanomaterials, even at low levels, can alter the actin cytoskeleton of cells. There is a knowledge gap concerning how the actin cytoskeleton of cells is affected by low concentrations of nanomaterials, when cell viability and membrane integrity have not been changed. The overall research goal of this CAREER project is to determine how low-level metal-based nanoparticles affect the actin cytoskeleton in normal and cancer cells, and to apply this knowledge to tune their impact on the actin cytoskeleton for inhibition of cancer cell migration without impacting normal cells. The overarching hypothesis is that the interaction mechanism of metal-based nanoparticles with actin cytoskeleton will be dependent on their surface functionality and intracellular degradability, and these properties can be tuned to selectively disrupt the actin cytoskeleton in cancer cells without affecting the actin cytoskeleton in normal cells. Specifically, this project will focus on two model metal-based nanoparticles including metal-organic frameworks and gold nanoparticles. Objective 1 will determine how low-level metal-based nanoparticles affect the actin structures and functions of vascular cells. Objective 2 will reveal the mechanisms of how these nanoparticles alter the actin structures and migration ability of cancer cells. Finally, Objective 3 will predict and tune the impact of nanomaterials on the actin cytoskeleton in vascular and cancer cells by combining atomic force microscopy techniques with surface functionalization of nanoparticles. The actin cytoskeleton changes induced by the nanoparticles will be resolved by nanomechanical atomic force microscopy and super resolution fluorescence microscopy. The mechanistic knowledge generated from this research will lead to: (i) a sensitive platform for nanoparticle safety assessment that is based on the biophysical responses of vascular cells; and (ii) several versatile, effective, and safe approaches for stopping cancer metastasis. The educational objective of this project is to improve the retention of undergraduates in STEM education, by engaging first-year students to specific research tasks focusing on nano-bio interactions, conducting a workshop series entitled “SEE NANO” at Tribal Colleges, and bringing Flipped Classroom Methodology to STEM classrooms. The research integrated educational plan places a strong emphasis on educating First-Generation College Students and Native American Students, two underrepresented groups in South Dakota exhibiting high dropout rates after their first year. Engaging these students in research during their first summer will motivate and promote their academic persistence in completing STEM education. The PI will also integrate visually appealing and scientifically interesting research results with Flipped Classroom Methodology to make STEM classrooms more enjoyable and engaging, thereby promoting active learning and retention in STEM fields.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
由于纳米材料无意中释放到环境中(通过空气和水污染),或者有意地将纳米材料用于治疗癌症等疾病,纳米材料可能与人体细胞相互作用。细胞暴露于纳米材料可产生剂量依赖性的有益或有害影响。这些影响传统上是用生化分析来评估的,比如细胞活力和膜完整性分析。然而,这些方法忽略了纳米材料对细胞肌动蛋白细胞骨架(细胞的“骨结构”)的影响。这个CAREER项目将产生关于低水平金属基纳米颗粒如何影响正常细胞和癌细胞中的肌动蛋白细胞骨架的新知识。该项目的潜在影响将是为纳米材料的安全性评估提供一个基于肌动蛋白细胞骨架的敏感和定量平台,从而能够建立安全和可持续纳米材料的监管和制造框架。该项目还将潜在地为使用纳米材料治疗癌症转移(90%的人类癌症死亡的原因)带来安全、有效和通用的方法。该项目的研究综合教育计划非常重视教育第一代大学生和美国原住民学生,这是南达科他州两个代表性不足的群体,目前辍学率很高。通过精心策划的暑期研究经历,这两个小组的10名学生预计将在化学、生物学、材料科学和纳米生物技术领域获得宝贵的实践技能,并在完成STEM教育时增强学术毅力。PI还将在部落学院举办名为“SEE NANO”的系列研讨会,并将视觉吸引力和科学趣味性的研究成果与翻转课堂方法相结合,使STEM课堂更加愉快和引人入胜,从而促进STEM领域的主动学习和保留。大多数关于纳米材料细胞毒性的研究依赖于宏观生化分析,包括细胞活力和膜完整性分析,而没有考虑到纳米尺度与纳米材料的相互作用,即使是低水平的相互作用,也会改变细胞的肌动蛋白细胞骨架。在细胞活力和膜完整性没有改变的情况下,关于低浓度纳米材料如何影响细胞的肌动蛋白细胞骨架的知识还存在空白。CAREER项目的总体研究目标是确定低水平金属基纳米颗粒如何影响正常细胞和癌细胞中的肌动蛋白细胞骨架,并应用这些知识来调节它们对肌动蛋白细胞骨架的影响,从而在不影响正常细胞的情况下抑制癌细胞迁移。总体假设是,金属基纳米颗粒与肌动蛋白细胞骨架的相互作用机制将取决于它们的表面功能和细胞内降解性,这些特性可以被调整以选择性地破坏癌细胞中的肌动蛋白细胞骨架,而不影响正常细胞中的肌动蛋白细胞骨架。具体来说,该项目将重点研究两种模型金属基纳米颗粒,包括金属有机框架和金纳米颗粒。目的1将确定低水平金属基纳米颗粒如何影响血管细胞的肌动蛋白结构和功能。目的2将揭示这些纳米颗粒如何改变癌细胞的肌动蛋白结构和迁移能力的机制。最后,目的3将结合原子力显微镜技术和纳米颗粒的表面功能化,预测和调整纳米材料对血管细胞和癌细胞中肌动蛋白细胞骨架的影响。纳米颗粒引起的肌动蛋白细胞骨架变化将通过纳米力学原子力显微镜和超分辨率荧光显微镜进行解析。从这项研究中产生的机械知识将导致:(i)基于血管细胞的生物物理反应的纳米颗粒安全性评估的敏感平台;(ii)几种通用的、有效的、安全的阻止癌症转移的方法。该项目的教育目标是通过让一年级学生参与纳米生物相互作用的具体研究任务,在部落学院举办名为“SEE NANO”的系列研讨会,以及将翻转课堂方法引入STEM课堂,提高STEM教育本科生的保留率。这项研究综合教育计划非常重视教育第一代大学生和美国原住民学生,这是南达科他州两个代表性不足的群体,在第一年之后就表现出很高的辍学率。让这些学生在他们的第一个暑假参与研究将激励和促进他们在完成STEM教育方面的学术坚持。PI还将把具有视觉吸引力和科学趣味性的研究成果与翻转课堂方法相结合,使STEM课堂更加愉快和引人入胜,从而促进STEM领域的主动学习和保留。该奖项反映了美国国家科学基金会的法定使命,并通过使用基金会的知识价值和更广泛的影响审查标准进行评估,被认为值得支持。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Low-dose albumin-coated gold nanorods induce intercellular gaps on vascular endothelium by causing the contraction of cytoskeletal actin
- DOI:10.1016/j.jcis.2023.06.154
- 发表时间:2023-06-28
- 期刊:
- 影响因子:9.9
- 作者:Li,Zhengqiang;Liu,Jinyuan;Wang,Congzhou
- 通讯作者:Wang,Congzhou
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CONGZHOU WANG的其他文献
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